There have been increasingly developed many percutaneous absorption type pharmaceutical products in recent years for administration of a drug through the skin. Such percutaneous absorption type pharmaceutical products have been receiving high reputation in view of the utility of the administered drug, which is ensured by avoiding primary metabolism in the liver, sustention of pharmacological effect, compliance such as convenience of administration, confirmation of administration and the like. It is therefore advantageous for many other drugs if they can be administered by a method for percutaneous administration through the skin, particularly a drug administration method comprising use of a patch for adhering a drug-containing adhesive layer to the skin.
In the case of many drugs, however, its percutaneous absorbability is extremely low and, for the expected pharmacological effect of the drug to be expressed, the percutaneous absorbability of the drug needs to be improved by a method comprising adding an absorption enhancer represented by an organic liquid component (e.g., long chain fatty acid ester, long chain aliphatic alcohol etc.) to the adhesive layer of a patch, and the like.
The addition of an organic liquid component to an adhesive is extremely useful for improving percutaneous absorbability of the drug to be contained in the adhesive layer. However, when an organic liquid component is added in a large amount, the adhesive is excessively plasticized to reduce its cohesive power, which then causes problems in that the adhesive partially remains on the skin upon peeling off of the patch from the skin after adhesion (i.e., adhesive residue), and a part of the adhesive leaks out from the edge of the adhesive layer during preservation of a patch in a package (i.e., adhesive bleed) and adheres to the inside of the package, thereby preventing the patch from being taken out easily.
To prevent decrease of the cohesive power of an adhesive, the adhesive is generally crosslinked using various crosslinking agents such as isocyanate, metallic chelate compound, epoxy and the like. When an adhesive layer is formed, however, contact of the drug contained in the adhesive with the crosslinking agent results in a reaction of the crosslinking agent with the drug due to the extremely high reactivity of the crosslinking agent, which then causes modification of the crosslinking agent and/or the drug. Therefore, a crosslinking agent cannot be problematically used for prevention of decrease in the cohesive power of the drug-containing adhesive. When an adhesive is crosslinked using a crosslinking agent, drying of the adhesive at a high temperature, UV irradiation or an aging treatment comprising preservation at a high temperature for a certain time are generally preferable for the complete termination of crosslinking of the adhesive and for higher crosslinking degree. When the adhesive contains a drug, however, the stability of the drug contained in the adhesive is problematically disturbed by these treatments.
Accordingly, it is an object of the present invention to provide a patch that avoids problems such as adhesive residue and adhesive bleed, that facilitates addition of a percutaneous absorption agent and improves the percutaneous absorbability of the drug, as well as a production method thereof.